Live attenuated rotavirus vaccine for oral administration

Abstract

This invention provides liquid rotavirus formulations that are suitable for oral administration to human infants. In particular, the invention provides pharmaceutical compositions and vaccines, comprising a rotavirus antigen, a sugar and a carboxylate, wherein said formulation has a pH of between pH 5.0 and pH 8.0 and comprises no phosphate or less than 5 mM phosphate. The invention also provides methods of preparing said rotavirus formulations and use thereof in the prevention or treatment or rotavirus associated diseases in humans.

1. A liquid rotavirus immunogenic composition suitable for oral administration to a human infant, comprising a live attenuated rotavirus antigen, a sugar and a carboxylate wherein said formulation has a pH of between about pH 5.0 and about pH 8.0 and comprises less than 1 mM phosphate, wherein said carboxylate is a carboxylate salt of adipate. 
     
     
       2. The liquid composition according to  claim 1 , wherein said composition comprises less than 0.1 mM phosphate. 
     
     
       3. The liquid composition according to  claim 1 , wherein said composition is free of phosphate. 
     
     
       4. The liquid composition according to  claim 1 , wherein the pH of said composition is between about pH 5.5 to about pH 7.5. 
     
     
       5. The liquid composition according to  claim 4 , wherein the pH of said composition is between about pH 6.0 and about pH 7.0. 
     
     
       6. The liquid composition according to  claim 1 , wherein said carboxylate is present at a concentration of between about 50 mM and about 2 M. 
     
     
       7. The liquid composition according to  claim 6 , wherein said carboxylate is present at a concentration of between about 100 mM and about 1 M. 
     
     
       8. The liquid composition according to  claim 7 , wherein said carboxylate is present at a concentration of between about 400 mM and about 700 mM. 
     
     
       9. The liquid composition according to  claim 1 , wherein said sugar is selected from the list consisting of: glycerol, erythrose, erythriol, xylitol, arabitol, ribose, xylose, arabinose, glucose, tagalose, mannose, galactose, fructose, inositol, sorbitol, mannitol, galactitol, a combination of glucose and fructose, maltose, sophorose, lactose, cellobiose, melibiose, trehalose, sucrose, palatinose, maltulose, lactulose, maltitol, lactitol, raffinose, maltotriose, melezitose, cellotriose, ciritol, maltotetraose, stachyose, cellotetraose, maltopentaose, cellopentaose, maltohexaose, cellohexaose, oligosaccharides. 
     
     
       10. The liquid composition of  claim 9 , wherein said sugar is sucrose or dextrose. 
     
     
       11. The liquid composition according to  claim 1 , wherein the concentration of said sugar is between about 35% w/w and about 70% w/w. 
     
     
       12. The liquid composition according to  claim 11 , wherein the concentration of said sugar is between about 40% w/w and about 70% w/w. 
     
     
       13. The liquid composition according to  claim 12 , wherein the concentration of said sugar is between about 50% w/w and about 55% w/w. 
     
     
       14. The liquid composition according to  claim 1 , additionally comprising a carboxylic acid. 
     
     
       15. The liquid composition according to  claim 14 , wherein said carboxylic acid is adipic acid. 
     
     
       16. The liquid composition according to  claim 1 , further comprising calcium ions. 
     
     
       17. The liquid composition according to  claim 1 , wherein said live attenuated rotavirus is a live attenuated human rotavirus. 
     
     
       18. The liquid composition according to  claim 17 , wherein said live attenuated human rotavirus is selected from the group consisting of: HRV 89-1 2C2 strain deposited under accession number ATCC VR 2272, progeny, reassortants and immunologically active derivatives thereof; HRV P43 strain deposited under accession number ECACC 99081301, progeny, reassortants and immunologically active derivatives thereof. 
     
     
       19. The liquid composition according to  claim 1 , wherein said composition has an antacid capacity of at least 8 minutes as assessed by the Baby Rossett-Rice assay. 
     
     
       20. The liquid composition according to  claim 19 , wherein said composition has an antacid capacity of at least 12 minutes as assessed by the Baby Rossett-Rice assay. 
     
     
       21. The liquid composition according to  claim 1  wherein said composition is stable under at least one of the following conditions: for 7 days at 37° C., for one year at 4° C., for two years at 4° C. 
     
     
       22. The liquid composition according to  claim 1 , which is a vaccine. 
     
     
       23. The liquid composition as claimed in  claim 1 , wherein said composition is provided in a dose volume of between 0.2 ml and 2.0 ml. 
     
     
       24. The liquid composition as claimed in  claim 23 , wherein said composition is provided in a dose volume of between 0.5 ml and 1.5 ml. 
     
     
       25. A method of prevention of rotavirus associated diseases in humans by administering to a human subject in need thereof an effective amount of a liquid formulation according to  claim 1 . 
     
     
       26. The method as claimed in  claim 25 , comprising administering the liquid formulation for the prevention of rotavirus gastroenteritis in humans. 
     
     
       27. The method as claimed in  claim 26 , comprising administering the liquid formulation for prevention of rotavirus severe gastroenteritis in humans. 
     
     
       28. The method as claimed in  claim 26 , wherein said gastroenteritis or severe gastroenteritis is caused by a rotavirus strain of a different serotype from that of the rotavirus strain contained in said liquid formulation. 
     
     
       29. The method as claimed in  claim 25 , wherein said composition is provided in a dose volume of between 0.2 ml and 2.0 ml. 
     
     
       30. The method as claimed in  claim 29 , wherein said composition is provided in a dose volume of between 0.5 ml and 1.5 ml. 
     
     
       31. A method for the preparation of a liquid rotavirus composition according to  claim 1  comprising admixing a rotavirus antigen, a sugar and a carboxylate with a pharmaceutically acceptable diluent. 
     
     
       32. The method according to  claim 25 , wherein said prevention comprises administering two oral doses of a safe and effective amount of the human live attenuated rotavirus composition to an infant within 4-15 weeks of age at the time of dose 1. 
     
     
       33. The liquid composition according to  claim 1 , wherein said carboxylate is a carboxylate salt that is sodium adipate having the formula Na 2 C 6 H 8 O 4 .